Acoustic overexposures causing only temporary threshold shifts can cause permanent loss of auditory nerve (AN) fibers, despite no loss of cochlear hair cells. This primary neuropathy, seen as an immediate retraction of synaptic terminals on inner hair cells (IHC), followed by slow death of neuronal cell bodies, is selective for the subgroup of AN fibers with high thresholds and low spontaneous rates (SRs). This explains why ABR thresholds can recover despite loss of ~40% of AN fibers. Preliminary results suggest this neuropathy is elicited even by moderate-level exposure (84 dB SPL), especially in the absence of olivocochlear (OC) feedback, and that selective low-SR fiber loss may lead to hyperacusis, tinnitus and hyperactivity in central circuits. Recent human studies also suggest that low-SR neuropathy may be associated with tinnitus; and AN masking studies in animals suggest it should contribute to difficulties hearing in a noisy background. We pursue these clinically important issues, from cochlea to colliculus and from mouse to human, in five Specific Aims: Aim 1 uses the confocal to examine AN/IHC synapses in humans to ask whether the low/high SR dichotomy is present in our ears and to quantify primary neuropathy in the aging ear. Aim 2 is a neurophysiological study of masking in the AN of noise-damaged ears designed to assess the impact of low-SR neuropathy on coding of signals in noise and to develop an ABR-based assay to diagnose the loss of low-SR fibers. Aim 3 uses tract-tracing techniques to examine the central projections of low-SR fibers, to test the hypothesis that they represent the major ascending input to OC reflex circuitry. Aim 4 uses selective OC lesions to test the hypothesis that a major role of the OC system is to minimize primary neuropathy in everyday acoustic environments. Aim 5 combines neurophysiological studies of the inferior colliculus with behavioral measures based on the acoustic startle responses to test the hypothesis that low-SR neuropathy leads to central hyperactivity, hyperacusis and tinnitus.